Recently, numerous reports have appeared describing the presence of liver-cell adenomas in women using oral contraceptives. Animal studies conducted at the time these agents were originally tested foretold of the possibility but it was generally ignored. Since then, carcinogenesis has come to be viewed as a multistage process composed of two general stages, initiation and promotion. Circumstantial evidence suggests that chronic ingestion of oral contraceptive agents may act as a tumor promoting agent in the liver; however, they have never been tested using an initiation-promotion protocol. The objective of the present study is to evaluate the liver tumor promoting activity of two oral contraceptive agents, norethynodrel and mestranol. Female Sprague Dawley rats have been initiated by treatment with diethylnitrosamine twenty-four hours following a partial hepatectomy. One day later the rats were transferred to control diet, diet containing the known liver promoter, phenobarbital, or diets containing mestranol, norethynodrel or both these agents. Animals will be killed after 4, 6 and 9-12 months and histochemical analysis for gammaglutamyl transpeptidase positive foci of hepatocytes will be carried out. Other organs will be analyzed at sacrifice and where indicated, prepared for histopathological evaluation. Various biochemical analyses will be carried out to determine some of the acute effects of these agents on liver. In addition, the initiation potential of these agents will be evaluated using the short liver carcinogenesis assay described by Cayama et al. (Nature 275, 60-62, 1978) where the steriods will be used as the "carcinogen" in their protocol. The results of these studies should shed some new light on the "carcinogenic potential" of oral contraceptive agents in light of current theories on the mechanisms of carcinogenesis.